title: Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium.
abstract: Niemann-Pick type C1 (NPC1) disease is a neurodegenerative lysosomal storage disorder caused by mutations in the acidic compartment (which we define as the late endosome and the lysosome) protein, NPC1. The function of NPC1 is unknown, but when it is dysfunctional, sphingosine, glycosphingolipids, sphingomyelin and cholesterol accumulate. We have found that NPC1-mutant cells have a large reduction in the acidic compartment calcium store compared to wild-type cells. Chelating luminal endocytic calcium in normal cells with high-affinity Rhod-dextran induced an NPC disease cellular phenotype. In a drug-induced NPC disease cellular model, sphingosine storage in the acidic compartment led to calcium depletion in these organelles, which then resulted in cholesterol, sphingomyelin and glycosphingolipid storage in these compartments. Sphingosine storage is therefore an initiating factor in NPC1 disease pathogenesis that causes altered calcium homeostasis, leading to the secondary storage of sphingolipids and cholesterol. This unique calcium phenotype represents a new target for therapeutic intervention, as elevation of cytosolic calcium with curcumin normalized NPC1 disease cellular phenotypes and prolonged survival of the NPC1 mouse.
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK. (emyr.lloyd-evans@pharm.ox.ac.uk
authors.forename: Emyr
authors.initials: E
authors.lastname: Lloyd-Evans
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Morgan
authors.forename: Xingxuan
authors.initials: X
authors.lastname: He
authors.forename: David A
authors.initials: DA
authors.lastname: Smith
authors.forename: Elena
authors.initials: E
authors.lastname: Elliot-Smith
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Sillence
authors.forename: Grant C
authors.initials: GC
authors.lastname: Churchill
authors.forename: Edward H
authors.initials: EH
authors.lastname: Schuchman
authors.forename: Antony
authors.initials: A
authors.lastname: Galione
authors.forename: Frances M
authors.initials: FM
authors.lastname: Platt
mesh_terms: D000143:Acids; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D003474:Curcumin / Q000627:therapeutic use; D006028:Glycosphingolipids / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008247:Lysosomes / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000145:classification / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D013110:Sphingosine / Q000378:metabolism*
chemical_list: D000143:Acids; D002352:Carrier Proteins; D006028:Glycosphingolipids; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D002784:Cholesterol; D003474:Curcumin; D013110:Sphingosine; D002118:Calcium